07 Molecular and Cellular Biology Coleen T. Murphy, Ph.D. Slowing the Ticking Clock: C. elegans Screens for Reproductive Aging Regulators Human reproductive aging manifests itself in maternal age-related increases in infertility, miscarriage, and birth defects. We propose to develop methods to prevent and treat age- related reproductive problems. For this purpose, we have developed a C. elegans as a model of reproductive cessation, and we are using it to find mutants and chemical treatments that extend the reproductive period. The goals of our work are to (1) physiologically and molecularly characterize the cause of reproductive cessation in wild-type animals, (2) identify mutants that slow reproductive aging and maintain egg quality later in life, and (3) carry out a high-throughput screen for chemical compounds that slow reproductive aging. Thus far we have been able to determine the underlying cause of reproductive aging in C. elegans, decreased egg quality, which is also thought to be the underlying cause of human reproductive aging. Thus, our model has great potential to aid in the study of human reproductive aging. We have also identified a conserved TGF-ss pathway as a major regulator of reproductive aging, and have defined its downstream transcriptional effects. Finally, we have designed and carried out pilot screens to identify mutants with extended reproductive spans. In addition to the mutants we select in the screen, which represent possible new drug targets, we propose using a chemical genetic screen to identify candidate drugs for the treatment of age-related reproductive problems. Our screen will not only identify chemical compounds that can increase progeny viability, it will also determine the effect of these chemicals on the health of the mother. These approaches will expand our knowledge of the causes of reproductive aging, and will help identify candidates for the treatment and prevention of age-related reproductive decline.